Inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro. Mediation by metabolism to N-D-lactoylcysteine and induction of apoptosis.

L G Edwards, A Adesida, P J Thornalley

Index: Leuk. Res. 20 , 17-26, (1996)

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Abstract

The inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro is mediated by the inhibtion of de novo pyridimine synthesis. When S-D-lactoylglutathione was added to human leukaemia 60 cells in culture, it was hydrolysed by thiolesterase activity to reduced glutathione and D-lactate but also converted to N-D-lactoylcysteinylglycine and N-D-lactoylcysteine by gamma-glutamyl transferase and dipeptidase. The N-D-lactoylcysteine inhibited human leukaemia 60 cell growth: the median growth inhibitory concentration IC(50) value was 46.7 +/ -0.9 (N=30) and the median toxic concentration TC(50) value was 103 +/- 1 microM. Other N-(R)2-hydroxyacylcysteine derivatives, N-D-mandelylcysteine and N-L-glyceroylcysteine, were less effective inhibitors of human leukaemia 60 cell growth, whereas N-D-lactoylcysteine ethyl ester was more effective: the IC(50) value was 16.5 +/- 1.5 microM(N=8). Cytotoxic concentrations of S-D-lactoylglutathione-induced apoptosis in human leukaemia 60 cells. The S-D-lactoylglutathione was not toxic to peripheral human lymphocytes at the same concentrations but rather induced growth arrest. The expected mechanism of action of N-D-lactoylcysteine is inhibition of dihydro-orotase, which is particularly susceptible to inhibition by cysteine derivatives.